5-218381-G-T

Variant names:

• chr5-218381-G-T
• rs761508577
• NM_004168.4:c.26G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004168.4(SDHA):​c.26G>T​(p.Arg9Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R9W) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000038 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SDHA NM_004168.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.58
• Publications: 2 publications found

Genes affected

SDHA (HGNC:10680): (succinate dehydrogenase complex flavoprotein subunit A) This gene encodes a major catalytic subunit of succinate-ubiquinone oxidoreductase, a complex of the mitochondrial respiratory chain. The complex is composed of four nuclear-encoded subunits and is localized in the mitochondrial inner membrane. Mutations in this gene have been associated with a form of mitochondrial respiratory chain deficiency known as Leigh Syndrome. A pseudogene has been identified on chromosome 3q29. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2014]

ENSG00000286001 (HGNC:):

CCDC127 (HGNC:30520): (coiled-coil domain containing 127) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004168.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHA	NM_004168.4	MANE Select	c.26G>T	p.Arg9Leu	missense	Exon 1 of 15	NP_004159.2
	SDHA	NM_001294332.2		c.26G>T	p.Arg9Leu	missense	Exon 1 of 14	NP_001281261.1
	SDHA	NM_001330758.2		c.26G>T	p.Arg9Leu	missense	Exon 1 of 13	NP_001317687.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHA	ENST00000264932.11	TSL:1 MANE Select	c.26G>T	p.Arg9Leu	missense	Exon 1 of 15	ENSP00000264932.6
	ENSG00000286001	ENST00000651543.1		n.26G>T		non_coding_transcript_exon	Exon 1 of 24	ENSP00000499215.1
	SDHA	ENST00000510361.5	TSL:2	c.26G>T	p.Arg9Leu	missense	Exon 1 of 14	ENSP00000427703.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000900 AC: 1 AN: 111172 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000384 AC: 5 AN: 1303480 Hom.: 0 Cov.: 31 AF XY: 0.00000311 AC XY: 2 AN XY: 643704

African (AFR) AF: 0.00 AC: 0 AN: 26830

American (AMR) AF: 0.00 AC: 0 AN: 24980

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20254

East Asian (EAS) AF: 0.00 AC: 0 AN: 31022

South Asian (SAS) AF: 0.0000154 AC: 1 AN: 64986

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33668

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3668

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1044734

Other (OTH) AF: 0.0000750 AC: 4 AN: 53338

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000897 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pheochromocytoma/paraganglioma syndrome 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Uncertain:1

Feb 23, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SDHA protein function. ClinVar contains an entry for this variant (Variation ID: 839550). This variant has not been reported in the literature in individuals affected with SDHA-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 9 of the SDHA protein (p.Arg9Leu).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.0092	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	15
DANN	Benign	0.69
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.60	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.6
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.19
Sift	Benign	0.061	T
Sift4G	Benign	0.29	T
Polyphen		0.0040	B
Vest4		0.52
MutPred		0.71		Loss of methylation at R9 (P = 0.0231)
MVP		0.50
MPC		1.3
ClinPred		0.27	T
GERP RS		2.8
PromoterAI		0.047	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.13
gMVP		0.85
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs761508577; hg19: chr5-218496;